Skin implant and preparation method thereof

Abstract

The invention discloses a skin implant, the skin implant is a freeze-drying agent, the freeze-drying agent is prepared from the following components in parts by weight: 2-15 parts of a PEG-PLA copolymer and 0.05-4.0 parts of hyaluronate, the PEG-PLA copolymer is prepared from a single-terminal hydroxyl polyethylene glycol compound and lactide through a polymerization reaction, and the hyaluronate is prepared from the following components in parts by weight: 1-10 parts of a cross-linking agent, 1-10 parts of a cross-linking agent, 1-10 parts of a cross-linking agent and 1-10 parts of a cross-linking agent. The mass ratio of the single-end hydroxyl polyethylene glycol to the lactide is (2.0-8.5): 1, and the molecular weight of the hyaluronate is 10-100 WDa. The skin implant provided by the invention has an excellent redissolution speed and can be quickly redissolved within 10 minutes, and the quick redissolution characteristic of the freeze-drying agent greatly facilitates clinical operation and shortens the preoperative preparation time.

Description

Technical Field

[0001] This invention belongs to the field of medical aesthetics, specifically relating to a skin implant, its preparation method, and its application. Background Technology

[0002] For most people, wrinkles appear when the ability to produce collagen decreases due to aging. To improve wrinkles, various materials are used as skin implants or fillers. Hyaluronic acid fillers account for more than 90% of the global filler market. However, hyaluronic acid fillers do not have the function of stimulating collagen production in the dermis.

[0003] Clear evidence exists that lactic acid promotes collagen production; therefore, materials containing lactic acid can be used in cosmetic medicine for filling in relevant areas and stimulating collagen production. Related products are already on the market, the most representative being poly-L-lactic acid (PLLA). PLLA can slowly degrade into lactic acid in the physiological environment, thus achieving lactic acid's function. Although PLLA has very high biocompatibility, due to its hydrophobic properties, it is usually prepared as micron-sized particles or microspheres for filling in human areas. Because microspheres have issues such as unsuitable size and poor aqueous dispersion, they are prone to aggregation during injection, leading to needle blockage, increasing the difficulty of the procedure for doctors and the pain for patients.

[0004] Polyethylene glycol (PEG) is widely used as a hydrophilic block copolymer due to its excellent hydrophilicity and biocompatibility. It avoids recognition and capture by the reticuloendothelial system (RES), liver, spleen, kidneys, and other organs in vivo, resulting in a longer blood circulation time. Chinese invention patent CN116102721A discloses a PEG-poly(L-lactic acid) copolymer. This copolymer contains both hydrophilic and hydrophobic segments, has no peptide chains, is non-immunogenic, and is easily biodegraded into metabolic products that are readily excreted without accumulation. However, PEG-poly(L-lactic acid) copolymer exhibits significant cytotoxicity when used alone, resulting in poor safety. Chinese invention patent CN119055555A provides a composite solution of PEG-PLA copolymer, which combines PEG-PLA copolymer and hyaluronic acid. The two components have a synergistic effect, reducing cytotoxicity and improving safety compared to single-component solutions. However, this composite solution exhibits poor stability during storage and is prone to degradation, producing free lactic acid.

[0005] Therefore, there is an urgent need in this field to develop a medical aesthetic material that is highly safe and stable and has excellent collagen regeneration effects. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a skin implant, which is a lyophilized agent. This solves the problems of poor safety and stability of PEG-PLA copolymers in the prior art, and ultimately produces a skin implant with high safety and good stability and excellent collagen regeneration effect.

[0007] To achieve the above-mentioned objective, the present invention provides a skin implant, characterized in that the skin implant is a lyophilized agent, the lyophilized agent comprising the following components in parts by weight: 2-15 parts of PEG-PLA copolymer and 0.05-4.0 parts of hyaluronic acid salt, wherein the PEG-PLA copolymer is obtained by polymerization of a hydroxyl-terminated polyethylene glycol compound and lactide, wherein the mass ratio of the hydroxyl-terminated polyethylene glycol to lactide is (2.0-8.5):1, and the molecular weight of the hyaluronic acid salt is 10-100 WDa.

[0008] In some embodiments, the single-hydroxyl-terminated polyethylene glycol compound is a polyethylene glycol monoalkyl ether; preferably, the polyethylene glycol monoalkyl ether is a polyethylene glycol monoC1-6 alkyl ether; more preferably, the polyethylene glycol monoC1-6 alkyl ether is a polyethylene glycol monomethyl ether; wherein the molecular weight of the polyethylene glycol monomethyl ether is 1000~10000 Da, for example 5000 Da.

[0009] In some embodiments, the lactide is selected from at least one of L-lactide, D-lactide, and D,L-lactide; preferably, the lactide is L-lactide.

[0010] In some embodiments, the hyaluronic acid salt is selected from at least one of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, and zinc hyaluronate; preferably, the hyaluronic acid salt is sodium hyaluronate.

[0011] In some embodiments, the PEG-PLA copolymer is 3 to 12 parts by weight; the hyaluronic acid salt is 0.1 to 3.0 parts by weight; preferably, the PEG-PLA copolymer is 3 to 10 parts by weight; the hyaluronic acid salt is 0.1 to 2.0 parts by weight; more preferably, the PEG-PLA copolymer is 3 to 10 parts by weight; the hyaluronic acid salt is 0.5 to 1.0 parts by weight, for example, the PEG-PLA copolymer is 6.55 parts by weight; the hyaluronic acid salt is 0.5 parts by weight.

[0012] In some embodiments, the mass ratio of the hydroxyl-terminated polyethylene glycol to lactide is (2.0~7.5):1; preferably, the mass ratio of the hydroxyl-terminated polyethylene glycol to lactide is (2.3~6.0):1, for example, 7:3, 4:2 or 17:3, etc.

[0013] In some embodiments, the molecular weight of the hyaluronic acid salt is 10-70 WDa; preferably, the molecular weight of the hyaluronic acid salt is 10-40 WDa and / or 60-70 WDa; more preferably, the molecular weight of the hyaluronic acid salt is 10-40 WDa or 60-70 WDa.

[0014] In some embodiments, the lyophilizing agent further includes a buffer salt, wherein the buffer salt causes the pH value of the lyophilizing agent after resolvation in water to be 5.5 to 8.5, preferably 6 to 8, for example 7.0; preferably, the buffer salt causes the osmotic pressure of the lyophilizing agent after resolvation in water to be 250 to 450 mOsmol / kg, preferably 250 to 350 mOsmol / kg, for example 300 mOsmol / kg.

[0015] In a preferred embodiment, the buffer salt is selected from any one or a combination of phosphate, citrate, sodium chloride, and pH adjuster; more preferably, the buffer salt is selected from a combination of phosphate and pH adjuster.

[0016] Wherein, the phosphate is selected from any one or a combination of dihydrogen phosphate and dihydrogen phosphate; the pH adjuster includes acidic pH adjusters and alkaline pH adjusters; preferably, the dihydrogen phosphate is selected from at least one of disodium hydrogen phosphate and dipotassium hydrogen phosphate; the dihydrogen phosphate is selected from at least one of sodium dihydrogen phosphate and potassium dihydrogen phosphate; the acidic pH adjuster is hydrochloric acid; and the alkaline pH adjuster is sodium hydroxide.

[0017] In a preferred embodiment, the buffer salt is selected from a combination of disodium hydrogen phosphate and sodium hydroxide.

[0018] In a preferred embodiment, the mass ratio of the PEG-PLA copolymer to the buffer salt is (1~10):1; more preferably (2~5):1, for example (3~4):1.

[0019] The present invention also provides a method for preparing the skin implant as described above, characterized in that PEG-PLA copolymer, hyaluronic acid salt, and buffer salt are mixed in water in the proportions described in the claims to obtain a complex solution; the complex solution is freeze-dried to obtain a lyophilized agent.

[0020] In some embodiments, the polymerization reaction is carried out in the presence of a catalyst; preferably, the catalyst is a tin-based metal catalyst, more preferably selected from at least one of dibutyltin diacetate, dibutyltin dibenzoate, tri-n-butylmethoxytin, dibutyltin dilaurate, stannous octanoate, stannous octanoate, and stannous isooctanoate; preferably, the catalyst accounts for 0.01% to 0.03% of the mass percentage of the polymerization reaction system, more preferably 0.02% to 0.03%.

[0021] In some embodiments, the polymerization reaction is carried out under anaerobic conditions.

[0022] In some embodiments, the polymerization reaction is carried out at a temperature of 70–150°C, preferably 90–135°C, and more preferably 100–130°C.

[0023] In some embodiments, the polymerization reaction takes 8 to 20 hours, preferably 11 to 16 hours.

[0024] In some embodiments, the polymerization reaction is further followed by purification and / or drying operations.

[0025] The present invention also provides the use of the skin implant described above in the preparation of medical aesthetic fillers, skin regeneration promoters or collagen stimulants for subcutaneous injection.

[0026] In some embodiments, the cosmetic filler is used to improve or correct volume loss or contour defects in the dermis and subcutaneous tissue selected from the face, neck, and hands; the skin regeneration promoter is used to improve skin quality, the improvement being selected from one or more of: increasing skin elasticity, improving skin firmness, improving skin smoothness, reducing pore appearance, and increasing dermal thickness; the collagen stimulant is used to treat or improve collagen loss or structural disorder caused by aging, photodamage, acne scars, or traumatic scars.

[0027] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of this application.

[0028] The reagents and raw materials used in this invention are all commercially available.

[0029] Compared with the prior art, the present invention has the following beneficial technical effects: 1) The skin implant (lyophilized agent) provided by the present invention has an excellent reconstitution speed and can be rapidly reconstituted within 10 minutes. The rapid reconstitution characteristic of the lyophilized agent greatly facilitates clinical operation and shortens the preoperative preparation time. 2) By preparing a lyophilized agent from a complex of PEG-PLA copolymer and hyaluronic acid salt, the problems of easy degradation and poor stability in the liquid state were effectively solved. This proves that the lyophilization process significantly inhibits polymer degradation, extends the effective storage period of the product, and ensures the long-term stability of product quality. 3) This invention significantly reduces the cytotoxicity of the material itself by precisely controlling the ratio of PEG-PLA copolymer to hyaluronic acid salt; 4) The lyophilized agent of the present invention exhibits strong total antioxidant capacity. This property helps to neutralize the oxidative stress response that may occur at the injection site, reduce inflammation, protect cells, and may synergistically promote tissue repair and regeneration. Attached Figure Description

[0030] Figure 1 This is an image of the lyophilized agent prepared in Example 1 before reconstitution; Figure 2 The image shows the appearance of the lyophilized agent prepared in Example 1 after reconstitution. Figure 3 This is a photograph taken after the injection to observe the results. Figure 4 The image shows the results of the injection 2 days after the procedure. Figure 5 Tissue samples for HE staining observation; Figure 6 This is a schematic diagram showing the area ratio of collagen fibers; Figure 7 Tissue samples for observation using Masson staining; Figure 8 This is a diagram showing the skin thickness of the implantation area. Detailed Implementation

[0031] The present application is further illustrated below by way of embodiments, but these embodiments are not intended to limit the scope of the present application. Experimental methods not specifically described in the following embodiments are performed according to conventional methods and conditions, or as selected in accordance with the product instructions.

[0032] The reagents and raw materials used in the following examples are all commercially available, and the reagents used are of injection grade purity.

[0033] Preparation of PEG-PLA copolymer

[0034] Polyethylene glycol monomethyl ether (molecular weight 5000 Da) and L-lactide were weighed in a ratio of 80:20 and added to a round-bottom flask. The flask was maintained in a 90°C oil bath with stirring. After complete melting, the mixture was evacuated for approximately 30 minutes. Stannous octoate was then added as a catalyst, and evacuation continued for approximately 30 minutes until no bubbles appeared. The mass percentage of stannous octoate in the total amount of polyethylene glycol monomethyl ether and L-lactide was 0.02%. The temperature was adjusted to 110°C, and the reaction was carried out for 12 hours to obtain crude PEG-PLA copolymer. Dichloromethane was added to the crude PEG-PLA copolymer, and the mixture was shaken to remove unreacted monomers. Excess dichloromethane was then added, and the mixture was stirred until the copolymer was completely dissolved. The mass-to-volume ratio of crude PEG-PLA copolymer to dichloromethane was 1 g / mL. Activated carbon (mass-to-volume ratio of 100 g / L to the adsorbed system) was then added, and the mixture was stirred for 30 minutes. The activated carbon was then removed by filtration, and the filter membrane had a pore size of 0.22 μm. Isopropyl ether was added to the product solution and stirred thoroughly until the copolymer was completely precipitated. The volume ratio of dichloromethane to isopropyl ether was 1:6. The mixture was filtered and the product was placed in an oven at 35°C and dried for about 24 hours to obtain PEG-PLA copolymer 1.

[0035] PEG-PLA copolymer 2-4 The only difference between the preparation of PEG-PLA copolymer 1 and the preparation of PEG-PLA copolymer 1 is the mass ratio of polyethylene glycol monomethyl ether to L-lactide, as shown in Table 1.

[0036] Table 1

[0037] Preparation of lyophilizing agent Example

[0038] Sodium hyaluronate (molecular weight 10-40 WDa) and PEG-PLA copolymer were added to phosphate buffer (disodium hydrogen phosphate solution) to prepare a solution of 0.5 wt% sodium hyaluronate and 6.55 wt% PEG-PLA. The pH was adjusted using sodium hydroxide to maintain an osmotic pressure of 250-350 mOsmol / kg and a pH of 6-8. The solution was then filtered through 0.45 μm and 0.22 μm filter membranes to obtain the complex solution.

[0039] The complex solution was freeze-dried according to the freeze-drying parameters in Table 2 and then sterilized by irradiation to obtain the final product.

[0040] Table 2

[0041] Examples 2-4 and Comparative Examples 1-3

[0042] Compared with Example 1, the only differences are the type and concentration of each component of the PEG-PLA copolymer in the complex solution, the molecular weight of sodium hyaluronate, and whether it is lyophilized. Other conditions and parameters are the same as in Example 1. Please see Table 3 for details.

[0043] Table 3

[0044] Example 1: Physical Properties Experiment of Lyophilizing Agent

[0045] Record the lyophilized state of Examples 1-3 and Comparative Examples 4-5, and weigh 338 mg of the lyophilized agent of each example and mix it thoroughly with 4 mL of sterile water for injection. Record the reconstitution time. See Table 4 for details.

[0046] Table 4

[0047] The physical properties of the lyophilized agent prepared in Example 1 before and after reconstitution are shown in the figures below. Figure 1 and Figure 2 As can be seen from the figure, the lyophilized agent in Example 1 was a white spongy solid before reconstitution and a clear solution after reconstitution.

[0048] As can be seen from Examples 1-3 and Comparative Example 4 above, when using high molecular weight sodium hyaluronate (e.g., 130 WDa, Comparative Example 4) as the lyophilized agent, the reconstitution time exceeds 20 minutes. However, when using low molecular weight sodium hyaluronate (e.g., 10-70 Da, preferably 10-40 WDa) as the raw material, the resulting lyophilized agent can be rapidly reconstituted within 10 minutes, significantly shortening the reconstitution time. Therefore, the skin implant (lyophilized agent) provided by this invention has an excellent reconstitution speed. The rapid reconstitution characteristic of this lyophilized agent greatly facilitates clinical operation and shortens preoperative preparation time.

[0049] In addition, this invention clarifies the synthesis method and freeze-drying process parameters of PEG-PLA copolymer. By optimizing the catalyst, reaction conditions, and using specific freeze-drying curves (including annealing processes), it is possible to stably and repeatedly prepare high-quality freeze-dried agents with fine texture, no lumps, and no collapse. The production process is highly controllable and has the potential for industrial production.

[0050] Example 2 Degradation Experiment

[0051] Multiple bottles of the complex solution from Comparative Example 3 (prepared in vials) were placed at 37°C for in vitro lactic acid degradation experiments. One bottle was taken out at different times, filtered through a 0.45 μm microporous membrane, and the free lactic acid content in the samples was determined. Three parallel samples were tested, and the average value was measured. See Table 5 for details.

[0052] Table 5

[0053] As the storage time increased, the free lactic acid content in the complex solution of Comparative Example 3 increased significantly. After 71 days, all polylactic acid in the PEG-PLA copolymer was degraded.

[0054] Multiple vials of the lyophilized reagent from Example 1 (prepared in vials) were placed at 37°C for in vitro lactic acid degradation experiments. One vial was taken out at different times, and 338 mg of the lyophilized reagent was thoroughly mixed with 4 mL of sterile water for injection. The mixture was filtered through a 0.45 μm microporous membrane, and the free lactic acid content in the sample was determined. Three parallel samples were tested, and the average value was calculated. See Table 6 for details.

[0055] Table 6

[0056] As the storage time increased, the free lactic acid content in the lyophilizer of Example 1 did not increase significantly. Only 3.21% of the polylactic acid in the PEG-PLA copolymer degraded after 90 days. Therefore, by preparing a lyophilizer from the complex of PEG-PLA copolymer and hyaluronic acid, the problems of easy degradation and poor stability in the liquid state (Comparative Example 3) were effectively solved. The preparation of the lyophilizer of this invention extends the effective storage period of the product and ensures long-term stability of product quality.

[0057] Example 3: Cytotoxicity Detection

[0058] Mouse fibroblasts L929 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences and cultured in MEM medium containing 10% serum and 1% penicillin and streptomycin.

[0059] Preparation of test samples: Using complete culture medium as a diluent, dilute the lyophilized reconstituted solution (338 mg of lyophilized agent reconstituted with 4 mL of sterile water for injection) and the non-lyophilized composite solution 5 times, shake on a shaker for 24 hours (37°C, 150 rpm), and take 100 μL as the test sample.

[0060] Mouse fibroblast L929 cells were cultured in MEM medium containing 10% serum and 1% penicillin and streptomycin, and incubated at 37°C and 5% CO2 until the cells reached stable growth. Cells were then seeded at a density of 1×10⁴ cells / well in 96-well cell culture plates. After 24 hours, the plates were washed once with PBS, and the prepared test samples were added, with three replicates for each sample. After 24 hours of incubation, the medium was discarded, and the plates were washed once with PBS. 50 μL of MTT reagent (prepared with blank medium at a concentration of 1 mg / mL) was added to each well. The plates were incubated for 2 hours, the medium was discarded, and 100 μL of isopropanol was added to each well. The plates were shaken for 2 minutes, and the absorbance at 570 nm was measured. Cell viability was calculated based on the results, which are shown in Table 7.

[0061] Table 7

[0062] This invention significantly reduces the cytotoxicity of the material itself by precisely controlling the ratio of PEG-PLA copolymer to sodium hyaluronate. The results of Example 3 show that the lyophilized agents within the preferred ratio range of this invention (such as Examples 1-3) exhibited a cell survival rate of over 70% in their reconstituted solutions for L929 cells, demonstrating excellent safety. However, formulations outside the preferred range (such as Comparative Examples 1 and 2) showed a significant decrease in cell survival. Furthermore, the lyophilized agents maintained stable safety after 3 months of storage at room temperature. In contrast, the un-lyophilized (Comparative Example 3) complex solution produced a large amount of free lactic acid upon being left at room temperature, significantly reducing the relative cell activity.

[0063] Furthermore, while Comparative Example 5 also exhibited excellent cell activity, the 90:10 PEG-PLA copolymer ratio, due to its low PLA content, may have resulted in insufficient total lactic acid release or a short release cycle, making it difficult to trigger a sufficient and sustained collagen regeneration response. In contrast, the 85:15, 80:20, and 70:30 PEG-PLA copolymer ratios, by increasing the PLA content, ensured that the copolymer had an appropriate degradation cycle. This allowed the lactic acid release curve to better match the physiological processes of tissue repair, collagen synthesis, and remodeling, thereby achieving a longer-lasting and more significant effect on volume maintenance and skin texture improvement.

[0064] Example 4: Antioxidant Capacity Determination

[0065] The Prussian blue method was used. Take 1 mL of the lyophilized reagent reconstituted in the examples (338 mg of lyophilized reagent reconstituted with 4 mL of sterile water for injection), add 2.5 mL of pH 6.6 phosphate buffer and 2.5 mL of 1% potassium ferricyanide (K3Fe(CN)6) solution, mix, and incubate at 50°C for 20 min. Add 2.5 mL of 10% trichloroacetic acid solution and mix. Take 2.5 mL of the mixture, add 2.5 mL of distilled water and 2.5 mL of 0.1% ferric chloride, mix well, let stand for 10 min, and measure the absorbance at 700 nm. Calculate the total antioxidant capacity. The results are shown in Table 8.

[0066] Table 8

[0067] These results demonstrate that the lyophilized agent of the present invention exhibits a strong total antioxidant capacity (both Examples 1 and 3 exceed 117%). This property helps neutralize oxidative stress that may occur at the injection site, reduces inflammation, protects cells, and may synergistically promote tissue repair and regeneration—functional advantages not possessed by existing PLLA microparticles or conventional fillers.

[0068] Example 5: Animal Experiments

[0069] To verify the effectiveness of the lyophilizer in Example 1 of this invention, animal experiments were conducted. New Zealand rabbits were used as experimental animals. The degradation performance and safety of the lyophilizer in Example 1 of this application were evaluated through subcutaneous implantation in the animal's back. Experimental groups 1, 2, and 3 were parallel samples of Example 1.

[0070] Anesthesia was administered via intravenous injection of 0.3% sodium pentobarbital at 1 mL / kg via the marginal ear vein. After anesthesia took effect, the animals were fixed in the rabbit platform, and their backs were shaved and prepared. Using the spine as the midline, one injection area was marked on each side of the back, and each area was further divided into two sites. The corresponding implant was injected intradermally according to the group, with 0.2 mL injected at each site. The injection sites were of similar depth and spaced at least 3 cm apart. Rabbits in the control group received no implant. Three weeks after implantation, rabbits in both the control and implant groups were sacrificed, and transepidermal water loss (TEWL) was measured using a vaporometer. Tissue sections were prepared and stained with hematoxylin and eosin (HE) and Masson's stain to observe inflammatory response, dermal thickness, tissue composition, and collagen levels.

[0071] Implantation observation. Immediately after injection, take photographs for observation. Figure 3 The implantation area showed a noticeable bulge, with no leakage of the injected fluid. Photos were taken 2 days post-injection for observation. Figure 4 The wheal disappeared in the implantation area, becoming invisible to the naked eye and without any noticeable sensation. No redness, swelling, inflammation, or other irritating reactions occurred in the implantation area.

[0072] Transdermal water loss value. As shown in Table 9, the transdermal water loss value of the skin implanted with this sample was significantly lower than that of the control group without this sample, indicating that the product of this invention can effectively improve the skin barrier function and increase skin hydration.

[0073] Table 9

[0074] HE staining observation. As shown in Table 10, the blank group showed no visible pathological changes, no inflammatory infiltration, and no granulation tissue formation. The histological evaluation score of the test samples was less than 3.0, indicating no irritation and suggesting complete degradation of the implant. Gross observation showed that all tissue samples had been absorbed without residue, and microscopic observation showed that all tissue samples had been absorbed without residue (see...). Figure 5 The implant was completely absorbed, and HE staining showed a low tissue inflammation score, indicating excellent biocompatibility of the material.

[0075] Table 10 HE staining inflammation score

[0076] Note: Scores less than 3 are recorded as no stimulation.

[0077] Masson staining observation: Collagen fibers appear blue, cell nuclei are bluish-brown, and other parts appear red. Three sections filled with cells were randomly selected from each slide under a 200x microscope. The mean percentage of collagen-positive area to total tissue area in the three sections was calculated using software. The results are shown in Table 11. Figure 6 As shown. Full-scale observation revealed a significant increase in the thickness of the dermal reticular layer in the experimental group (see...). Figure 7).

[0078] Table 11. Percentage of Collagen Fiber Area

[0079] Note: Compared with the control group, the experimental group showed P < 0.01 and P < 0.05.

[0080] Skin thickness observation. Skin tissue from the implantation area was selected for skin thickness measurement; the results are as follows: Figure 8 As shown, the cortical thickness of the experimental group was significantly greater than that of the control group.

[0081] The above animal experiments demonstrate the safety, skin's water retention capacity, and skin texture improvement properties of the implant of this invention, including increased dermal collagen production, increased dermal thickness, and thus improved skin texture.

[0082] Masson staining and quantitative analysis showed that the proportion of collagen fiber area and the thickness of the dermis in the implantation area were significantly increased (Table 11). Figures 6-8 This confirms that the product of this invention can effectively stimulate the regeneration and reorganization of autologous collagen, thereby achieving long-term, natural filling and skin rejuvenation effects.

[0083] In summary, the product of this invention not only achieves volume filling, but also substantially improves skin elasticity, firmness, and smoothness.

[0084] This invention combines a unique PEG-PLA copolymer and low molecular weight hyaluronic acid salt composite system with an optimized freeze-drying process, successfully solving problems such as slow reconstitution, easy sedimentation and needle blockage, and unstable liquid storage that exist in similar products. At the same time, it endows the product with multiple synergistic advantages such as rapid reconstitution, high stability, low cytotoxicity, antioxidant properties, and efficient promotion of collagen regeneration, providing the medical aesthetics field with a new type of skin implant that is safer, more effective, and more convenient to use.

[0085] Finally, it should be noted that the terms “comprising,” “including,” or any other variations thereof in this application are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0086] Although this application has been disclosed above through the description of specific embodiments, it should be understood that those skilled in the art can devise various modifications, improvements, or equivalents to this application within the spirit and scope of the appended solutions. Such modifications, improvements, or equivalents should also be considered to be included within the scope of protection claimed in this application.

Claims

1. A skin implant, characterized in that, The skin implant is a lyophilized agent, which comprises the following components in parts by weight: 2 to 15 parts of PEG-PLA copolymer and 0.05 to 4.0 parts of hyaluronic acid salt. The PEG-PLA copolymer is prepared by polymerization of a hydroxyl-terminated polyethylene glycol compound and lactide, wherein the mass ratio of the hydroxyl-terminated polyethylene glycol to lactide is (2.0 to 8.5):1, and the molecular weight of the hyaluronic acid salt is 10 to 100 WDa.

2. The skin implant as described in claim 1, characterized in that, The lyophilizing agent satisfies at least one of the following conditions (1) to (7): (1) The single-hydroxyl-terminated polyethylene glycol compound is a polyethylene glycol monoalkyl ether; (2) The lactide is selected from at least one of L-lactide, D-lactide and D,L-lactide; (3) The hyaluronic acid salt is selected from at least one of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, and zinc hyaluronate; (4) The PEG-PLA copolymer is 3 to 12 parts by weight; the hyaluronic acid salt is 0.1 to 3.0 parts by weight; (5) The mass ratio of the single-hydroxyl-terminated polyethylene glycol to lactide is (2.0~7.5):1; (6) The molecular weight of the hyaluronic acid salt is 10~70WDa; (7) The lyophilizing agent also includes a buffer salt, which makes the pH value of the lyophilizing agent after resolution in water 5.5 to 8.

5.

3. The skin implant as described in claim 2, characterized in that, The lyophilizing agent satisfies at least one of the following conditions (1) to (7): (1) The polyethylene glycol monoalkyl ether is polyethylene glycol monocarbonate. 1-6 Alkyl ethers; (2) The lactide is L-lactide; (3) The hyaluronic acid salt is sodium hyaluronate; (4) The PEG-PLA copolymer is 3 to 10 parts by weight; the hyaluronic acid salt is 0.1 to 2.0 parts by weight; (5) The mass ratio of the single-hydroxyl-terminated polyethylene glycol to lactide is (2.3~6.0):1; (6) The molecular weight of the hyaluronic acid salt is 10~40WDa and / or 60~70WDa; (7) The buffer salt makes the osmotic pressure of the lyophilized agent after resolution in water 250~450mOsmol / kg.

4. The skin implant as described in claim 3, characterized in that, The lyophilizing agent satisfies at least one of the following conditions (1) to (6): (1) The polyethylene glycol mono-C 1-6 Alkyl ether is polyethylene glycol monomethyl ether; (2) The PEG-PLA copolymer is 3 to 10 parts by weight; the hyaluronic acid salt is 0.5 to 1.0 parts by weight; (3) The molecular weight of the hyaluronic acid salt is 10~40WDa or 60~70WDa; (4) The buffer salt makes the osmotic pressure of the lyophilized agent after resolution in water 250~350mOsmol / kg; (5) The buffer salt is selected from any one or a combination of phosphate, citrate, sodium chloride, and pH adjuster; (6) The mass ratio of the PEG-PLA copolymer to the buffer salt is (1~10):

1.

5. The skin implant as described in claim 4, characterized in that, The lyophilizing agent satisfies at least one of the following conditions (1) to (5): (1) The molecular weight of the polyethylene glycol monomethyl ether is 1000~10000 Da; (2) The buffer salt is selected from a combination of phosphate and pH adjuster; (3) The phosphate is selected from any one or a combination of dihydrogen phosphate and dihydrogen phosphate; (4) The pH adjuster includes acidic pH adjusters and alkaline pH adjusters; (5) The mass ratio of the PEG-PLA copolymer to the buffer salt is (2~5):

1.

6. The skin implant as described in claim 5, characterized in that, The lyophilizing agent satisfies at least one of the following conditions (1) to (6): (1) The molecular weight of the polyethylene glycol monomethyl ether is 5000 Da; (2) The dihydrogen phosphate is selected from at least one of disodium hydrogen phosphate and dipotassium hydrogen phosphate; (3) The dihydrogen phosphate salt is selected from at least one of sodium dihydrogen phosphate and potassium dihydrogen phosphate; (4) The acidic pH adjuster is hydrochloric acid; (5) The alkaline pH adjuster is sodium hydroxide; (6) The mass ratio of the PEG-PLA copolymer to the buffer salt is (3~4):

1.

7. A method for preparing a skin implant as described in any one of claims 1 to 6, characterized in that, PEG-PLA copolymer, hyaluronic acid salt, and buffer salt are mixed in water in the proportions described in the claims to obtain a complex solution; the complex solution is then freeze-dried to obtain a lyophilized agent.

8. The method for preparing the skin implant as described in claim 7, characterized in that, The preparation method of the PEG-PLA copolymer satisfies at least one of the following conditions (1) to (5): (1) The polymerization reaction is carried out under the action of a catalyst; preferably, the catalyst is a tin-based metal catalyst, more preferably selected from at least one of dibutyltin diacetate, dibutyltin dibenzoate, tri-n-butyl methoxytin, dibutyltin dilaurate, stannous octoate, stannous octoate, and stannous isooctanoate; preferably, the catalyst accounts for 0.01% to 0.03% of the mass percentage of the polymerization reaction system, more preferably 0.02% to 0.03%; (2) The polymerization reaction is carried out under anaerobic conditions; (3) The polymerization reaction temperature is 70-150℃, preferably 90-135℃, and more preferably 100-130℃; (4) The polymerization reaction takes 8 to 20 hours, preferably 11 to 16 hours; (5) The polymerization reaction is further followed by purification and / or drying operations.

9. The use of a skin implant as described in any one of claims 1-6 in the preparation of a medical aesthetic filler, skin regeneration promoter, or collagen stimulant for subcutaneous injection.

10. The application as described in claim 9, characterized in that, The medical aesthetic filler is used to improve or correct volume loss or contour defects in the dermis and subcutaneous tissue selected from the face, neck, and hands; the skin regeneration promoter is used to improve skin quality, and the improvement is selected from one or more of the following: increasing skin elasticity, improving skin firmness, improving skin smoothness, reducing pore appearance, and increasing dermal layer thickness; the collagen stimulant is used to treat or improve collagen loss or structural disorder caused by aging, photodamage, acne scars, or traumatic scars.

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